An anti-infective synthetic peptide with dual antimicrobial and immunomodulatory activities.

Antibiotic-resistant infections are predicted to kill 10 million people per year by 2050, costing the global economy $100 trillion. Therefore, there is an urgent need to develop alternative technologies. We have engineered a synthetic peptide called clavanin-MO, derived from a marine tunicate antimicrobial peptide, which exhibits potent antimicrobial and immunomodulatory properties both in vitro and in vivo. The peptide effectively killed a panel of representative bacterial strains, including multidrug-resistant hospital isolates. Antimicrobial activity of the peptide was demonstrated in animal models, reducing bacterial counts by six orders of magnitude, and contributing to infection clearance. In addition, clavanin-MO was capable of modulating innate immunity by stimulating leukocyte recruitment to the site of infection, and production of immune mediators GM-CSF, IFN-γ and MCP-1, while suppressing an excessive and potentially harmful inflammatory response by increasing synthesis of anti-inflammatory cytokines such as IL-10 and repressing the levels of pro-inflammatory cytokines IL-12 and TNF-α. Finally, treatment with the peptide protected mice against otherwise lethal infections caused by both Gram-negative and -positive drug-resistant strains. The peptide presented here directly kills bacteria and further helps resolve infections through its immune modulatory properties. Peptide anti-infective therapeutics with combined antimicrobial and immunomodulatory properties represent a new approach to treat antibiotic-resistant infections.

Depressive symptoms and rates of bone loss at the hip in older men.

UNLABELLED: In this prospective cohort study, depressive symptoms were associated with higher rates of bone loss in older men. Poorer performance on physical function tests partly explained the association between depressive symptoms and bone loss, suggesting that efforts to increase exercise and improve physical performance in depressed men may be beneficial. INTRODUCTION: The aim of this study was to ascertain whether depressive symptoms are associated with increased rates of bone loss at the hip in older men. METHODS: A population-based prospective cohort study of 2,464 community-dwelling men, aged 68 and older, enrolled in the Osteoporosis in Men Sleep Ancillary Study had depressive symptoms assessed by the Geriatric Depression Scale (GDS). Subjects were categorized as depressed if GDS ≥6 at the initial examination. Bone mineral density (BMD) at the hip was measured using dual-energy X-ray absorptiometry at the initial and follow-up examination (average 3.4 years between exams). Use of antidepressant medications was assessed by interview and verified from medication containers at the two examinations. A computerized dictionary was used to categorize type of medication. RESULTS: In a base model adjusted for age, race/ethnicity, and clinic site, the mean total hip BMD decreased 0.70 %/year in 136 men with a GDS score of ≥6 compared to 0.39 %/year in 2,328 men with a GDS score of <6 (p = 0.001). Walking speed and timed chair stand partly explained the association between depressive symptoms and rates of bone loss. CONCLUSION: Depression, as defined by a score of 6 or greater on the Geriatric Depression Scale, is associated with an increased rate of bone loss at the hip in this cohort of older men. Adjustment for walking speed and timed chair stand attenuated the strength of the association, suggesting that differences in physical functioning do partially explain the observed association.

Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from in vitro and animal-based studies.

The regulation of bone metabolism continues to be an area of intense investigation, with recent evidence indicating a potential contribution from the neural system. In particular, the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) has been hypothesized to play a role in skeletal metabolism via its transporter (5-HTT). The 5-HTT is a plasma membrane transporter that is highly specific for the uptake of extracellular 5-HT, thereby facilitating the intracellular storage and/or degradation of 5-HT. The 5-HTT is clinically important as it is the key target of pharmaceutical agents aimed at treating affective disorders, such as major depressive disorder. By antagonizing the 5-HTT, selective serotonin reuptake inhibitors (SSRIs) potentiate 5-HT activity and effectively relieve the symptoms of depression. However, questions have been raised regarding the potential skeletal effects of SSRIs given the recent identification of a functional 5-HTT and functional 5-HT receptors in bone cells. This paper discusses the preclinical evidence for the skeletal effects of 5-HT and the inhibition of the 5-HTT. In particular, it discusses the: (1) role of 5-HT and the function of the 5-HTT; (2) presence of functional 5-HTTs in bone; (3) potential sources and response mechanisms for 5-HT in bone, and; (4) in vitro and in vivo skeletal effects of 5-HT and 5-HTT inhibition.

Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from clinical studies.

The discovery of a functional serotonin (5-hydroxytryptamine; 5-HT) transporter (5-HTT) in bone has given rise to questions about the physiologic role of 5-HT in bone, and the possible clinical implications for humans. 5-HT is known to play a role in the pathophysiology of depression, and many antidepressant medications function by inhibiting the 5-HTT. Among the antidepressants, those that selectively block the 5-HTT (namely, selective serotonin reuptake inhibitors; SSRIs) appear to have skeletal effects. Several studies have demonstrated lower bone density, increased rates of bone loss at the hip, and increased rates of fracture among older individuals taking SSRIs. However, there remains uncertainty about whether it is the antidepressant medications themselves or the reason for their use (depression) that is responsible for these observed bone changes. This paper reviews the epidemiologic literature that explores the role of the 5-HTT in bone health, by looking at questions about how depression, antidepressant therapy and SSRIs impact bone health in humans. Further research will be important to better understand how these factors interact to influence skeletal status, and to characterize the biochemical mechanism through which 5-HT may mediate bone turnover and metabolism.

Influence of menopause on mood: a systematic review of cohort studies.

OBJECTIVE: This systematic evidence review evaluates the independent influence of the menopausal transition on mood including depression, anxiety, and other psychological symptoms. METHODS: Community-based, prospective cohort studies of mid-life women transitioning through menopause that assessed at least one mood symptom on two or more occasions were identified by searches of MEDLINE (1966-2007) and PsycINFO (1974-2007) databases. Articles were selected based on predetermined inclusion and exclusion criteria. Each study was quality-rated by three authors; poor quality studies were excluded. RESULTS: Nine studies met inclusion criteria. They varied broadly in design, outcome measures, statistical methodology, and in consideration of and adjustment for important confounders. Five found no association between the menopausal transition and depression, negative mood, major depressive disorder, other psychological symptoms, and general mental health. Three found that women entering or completing the menopausal transition were more likely than premenopausal women to be depressed. One found that well-being increased from the early to late menopausal transition. CONCLUSION: There is no demonstrated pattern of an adverse independent influence of the menopausal transition on mood symptoms in mid-life women. However, the available studies are too methodologically diverse to be definitive.

Mid-trimester dilation and evacuation with laminaria does not increase the risk for severe subsequent pregnancy complications.

OBJECTIVE: To evaluate subsequent pregnancy outcomes in women with a previous mid-trimester (12-24 weeks) pregnancy termination by dilation and evacuation (D&E) as compared to women without a previous D&E. METHOD: Medical records for women who underwent a D&E between 1995 and 2003 were identified and reviewed. Women with subsequent pregnancies were compared on a 1:2 basis with women in a control group who had viable pregnancies and no previous mid-trimester DE. Outcomes of interest included preterm labor, placental abnormalities, and a composite complication outcome. RESULTS: Of the 317 women who underwent a D&E, 85 had viable subsequent pregnancies. These women delivered slightly earlier than the 170 controls (38.9 versus 39.5 weeks, p=0.001), although there was no statistically significant difference between the two groups with regard to birth weights, spontaneous preterm delivery, abnormal placentation, and overall complication rate. CONCLUSIONS: Mid-trimester termination by D&E does not increase the rate of clinically significant subsequent pregnancy complications.

Neutralization potential determination of siderite (FeCO3) using selected oxidants.

Siderite (FeCO3) is commonly found in coal overburden and, when present, can cause interference in the determination of neutralization potential (NP). Under acidic testing conditions, FeCO3 reacts to neutralize acid, which contributes to the NP. However, continued weathering of FeCO3 (oxidation of Fe2+ and hydrolysis of Fe3+) produces a neutral to slightly acidic solution. The effects of hydrogen peroxide (H2O2), potassium permanganate (KMnO4), and O2 on the laboratory measurement of NP of siderite samples taken from overburden were examined. All oxidation treatments lowered the NP values of the siderite samples as compared with the standard USEPA method. However, oxidation with H2O2 produced variable results depending on the amount of H2O2 added. Neutralization potential values obtained after oxidation treatments were highly correlated with Mn concentration. Reaction products (i.e., 2-line ferrihydrite) of siderite samples with H2O2 and KMnO4 were not representative of natural siderite weathering. Oxidation with O2 produced the lowest NP values for siderite samples. The reaction products produced by oxidation with O2 most closely represent those intermediate products formed when siderite is exposed to atmospheric weathering conditions. Oxidation with O2 also proved to be the most reproducible method for accurately assessing NP when siderite is present in overburden samples.

Vitamin D insufficiency in internal medicine residents.

Medical residents may be vulnerable to low vitamin D status because of long work hours and lack of sun exposure. We conducted a prospective cohort study to measure serum 25-hydroxyvitamin D concentrations among internal medicine residents, document seasonal variation in vitamin D status, and assess risk factors for inadequate vitamin D stores. Dietary intake of calcium and vitamin D, lifestyle characteristics, and serum concentrations of 25(OH)-vitamin D and intact parathyroid hormone (iPTH) were measured in 35 resident volunteers before and after the winter season. A total of 63-69% of medical residents consumed <400 IU/day of vitamin D; 61-67% consumed <1000 mg/day of calcium. Twenty-five (74%) had lower serum 25(OH)-vitamin D concentrations and 23 (68%) had higher serum iPTH in the spring than in the fall. Nine (26%) residents had serum concentrations of 25(OH)-vitamin D of <20 ng/mL in the fall; and sixteen (47%) in the spring. Seven residents (20%) had serum concentrations of 25(OH)-vitamin D of <20 ng/mL at both time-periods; Eighteen residents (51.4%) had 25(OH)-vitamin D levels of <20 ng/mL for at least one of the time-periods. Medical residents are at risk for hypovitaminosis D, particularly during the winter months and should be aware of the need to supplement their vitamin D stores. Insufficient vitamin D status and inadequate vitamin D intake may have long-term implications for bone health in these individuals. Increased educational efforts to promote healthy dietary and lifestyle choices that allow attainment and maintenance of skeletal health are appropriate in this population.

Ultrasound examination of the postpartum uterus: what is normal?

OBJECTIVE: To establish normal ultrasonographic findings for the postpartum uterus after vaginal delivery, and to characterize associated bleeding patterns. METHODS: Postpartum women were scanned by transabdominal ultrasound within 48 h after normal vaginal delivery. Uterine length, uterine width, endometrial stripe thickness and endometrial contents were evaluated by a single sonographer. Patients maintained a daily symptom diary for 6 weeks and were interviewed by telephone at 2 weeks. Statistical analysis was performed using chi2, Fisher's exact test, Student's t test and Pearson correlation. RESULTS: Mean endometrial stripe thickness was 1.1 +/- 0.6 cm, mean uterine length was 16.1 +/- 1.7 cm and mean uterine width was 8.7 +/- 1.0 cm. Postpartum bleeding requiring more than four protective pads per day for > or =10 days was associated with a thicker endometrial stripe (1.5 +/- 0.7 cm vs. 0.9 +/- 0.4 cm, p = 0.006). However, no patients experienced postpartum bleeding complications requiring intervention. Of the 40 women evaluated, 16 had echogenic material in the uterine cavity (mean size 12.7 +/- 6.9 cm2). The presence of echogenic material was not associated with the amount or duration of bleeding. CONCLUSIONS: Frequent postpartum ultrasonographic findings include a thickened endometrial stripe and echogenic material in the uterine cavity. The echogenic material commonly seen in the endometrial cavity of asymptomatic patients was not associated with the development of bleeding complications.

The prevalence and timing of cervical cerclage placement in multiple gestations.

OBJECTIVES: To investigate the prevalence and timing of cervical cerclage placement in multiple gestations. METHODS: Our perinatal database was queried for all multiple gestations delivered at Evanston Hospital from 12/95 through 12/00. This list was then cross-matched with billing and medical records for 'incompetent cervix' and 'cerclage.' The medical records of all deliveries /=14 weeks over a 5-year period. The number of patients that underwent cerclage placement was 29 or 3.6%. The mean gestational age at cerclage placement was 18.6+/-4.5 weeks (range 11-24.6). Twelve were elective or prophylactic while 17 were 'urgent' or 'emergent.' The mean gestational age for the 17 emergent cerclages was 21.4+/-2.2 weeks (range 16.6-24.6). When compared with those patients who did not undergo cerclage placement, there was no difference in maternal demographics including age, parity, or previous full-term delivery. There was a significant difference in the gestational age at delivery for the cerclage vs. no cerclage group; 29.3+/-5.6 vs. 34.4+/-4.6 weeks, respectively, and in the frequency of losses at

Lamellar body counts compared with traditional phospholipid analysis as an assay for evaluating fetal lung maturity.

OBJECTIVE: To compare lamellar body counts with the lecithin/sphingomyelin ratio and phosphatidylglycerol analysis in terms of assessment of risk of respiratory distress syndrome (RDS). METHODS: Lamellar body counts, lecithin-sphingomyelin ratios (L/Ss), and phosphatidylglycerol levels were assessed in 1611 amniotic fluid samples obtained at four clinical sites from pregnant women whose fetuses were at risk for RDS. Cases in which delivery occurred within 72 hours of sample collection (n = 833) were analyzed. Specific cutoffs for predicting the likelihood of RDS for both the lamellar body count and the L/S had been derived previously at each of the clinical sites based on receiver operating characteristic curves using unrelated samples, whereas phosphatidylglycerol was reported as either mature (present) or immature (absent). Standard clinical and radiographic criteria were used to diagnose RDS, and the diagnosis was confirmed by review of newborn records. RESULTS: One hundred (12.0%) of the 833 infants delivered within 72 hours of sample collection developed RDS. The negative predictive value of the lamellar body count (97.7%) was similar to that of the L/S (96.8%) and slightly better than that of phosphatidylglycerol analysis (94.7%) (P =.048). The lamellar body count performed as well as phospholipid analysis irrespective of gestational age or patient population. CONCLUSION: The lamellar body count compares favorably with traditional phospholipid analysis as an assay for assessment of fetal lung maturity. Lamellar body counts are preferable because they are faster, more objective, less labor intensive, less technique dependent, and less expensive and because they can be performed with equipment available in every hospital laboratory.

Should body size preference be a target of health promotion efforts to address the epidemic of obesity in Afro-Caribbean women?

OBJECTIVE: To determine if 1) Afro-Caribbean women prefer large body sizes, 2) the body size preference of Afro-Caribbean men and women are associated, 3) women's preferences are associated with increased risk of obesity or with weight management behaviors. DESIGN: Population samples of 314 and 487 women, ages 20-55 years, were recruited on Barbados and Dominica with response rates of 74% and 77%, respectively. Body size preferences, stress related variables, and demographic data were ascertained by questionnaire. Height and weight were also measured. On Barbados, body preference data were collected from male partners of participants, and data on intentions to perform weight management behaviors were collected from 175 women. RESULTS: Most women preferred body sizes within normal limits, although women on Dominica had a slightly larger ideal body size (IBS) than did Barbadian women (P<.05). On both islands, the size that women thought men preferred was related to their IBS (P<.0001). Likewise, IBS was associated with increased odds of being overweight (P<.001), however most overweight women (>75%) wanted to be smaller. IBS was not related to the intention to exercise or to eat high fat foods. CONCLUSIONS: It is unlikely that body size preference poses a barrier to intervention efforts to reduce the prevalence of overweight in Afro-Caribbean women.

Comparison of active phase labor between triplet, twin, and singleton gestations.

OBJECTIVE: To characterize the active phase of labor in triplet pregnancies and compare it with gestational age-matched twins and singletons. METHODS: Active phase rates were calculated beginning at 5 cm of dilation for women with triplet gestations longer than 24 weeks who labored and reached the second stage. Twin and singleton cohorts that also completed the first stage of labor were matched for gestational age at delivery (+/-1 week), parity, and epidural use. Intrapartum variables included oxytocin use (induction or augmentation, duration of infusion, and maximum dosage), cervical dilation at membrane rupture, and active phase dilation rate. RESULTS: Thirty-two triplet pregnancies met inclusion criteria between January 1994 and September 1998 and were each compared with twin and singleton cases in a 1:2 ratio. Triplet and twin active phase rates, while similar (1.8 versus 1.7 cm/hour, respectively), were significantly lower than the mean singleton dilation rate (2.3 cm/hour, P =.02). No other intrapartum variables differed between the three groups. Despite controlling for gestational age at delivery, mean birth weights were significantly higher in singletons and correspondingly lower in twins and triplets (2,493 versus 2,112 and 1,968 g, respectively; P =.001). An analysis of active phase dilation rates as a function of the cumulative birth weight per pregnancy demonstrated an inverse correlation, with slower progress in active labor associated with increasing total fetal weight (R = -.24; P =.002). CONCLUSIONS: Triplet and twin active phase dilation proceeds at a slower rate than that observed in singleton pregnancies. The rate of active phase dilation is inversely correlated to total fetal weight.

Optional vaginal delivery rate. An informative indicator of intrapartum care.

OBJECTIVE: To determine whether an "optional" vaginal delivery rate and novel delivery score would provide informative profiles of intrapartum care. STUDY DESIGN: Prospective survey of all parturients delivering between January and December 1996. Deliveries were categorized as standard-vaginal (V-S), optional-vaginal (V-O), standard-cesarean (C-S) or potentially avoidable-cesarean (C-PA) using specific perinatal criteria derived from the literature. A weighted equation was developed and applied, generating physician delivery scores, giving "extra credit" for V-O and a "debit" for C-PA: delivery score = [(% V-O x 2) + (% V-S) - (% C-PA] x 100. RESULTS: V-O rates and delivery scores ranged from 0% to 25% and from 52 to 113, respectively (medians of 9.8% and 92.9). Among the obstetricians (n = 38), a significant inverse correlation was noted between the total C-S rates and V-O rates (r = -.54, P < .005). The maternal-fetal medicine physicians (n = 6) had high total C-S rates (22-36%) but also had high V-O rates (17.1-23.5%) and high delivery scores (82.1-101.5). CONCLUSION: The optional vaginal delivery rate and delivery score are more-informative indicators of intrapartum management acumen than is cesarean section rate alone. We suggest incorporating these descriptors into departmental quality assurance programs.

Timing of labor induction after premature rupture of membranes between 32 and 36 weeks' gestation.

OBJECTIVE: The objective was to determine a consensus gestational age for labor induction after premature rupture of membranes between 32 and 36 weeks' gestation on the basis of the relative frequencies of adverse neonatal outcomes. STUDY DESIGN: A retrospective review was undertaken of all patients with premature rupture of membranes between 32 and 36 weeks' gestation. These patients were managed expectantly whenever possible. Neonatal outcomes were stratified by gestational age at rupture of membranes. RESULTS: Two hundred thirty-six patients with rupture of membranes between 32 and 36 weeks' gestation were managed expectantly. Prolongation of pregnancy by >/=1 week was infrequent in all cases, particularly if membrane rupture occurred after 34 weeks' gestation. Reductions in the neonatal length of stay and the incidence of hyperbilirubinemia were observed at 34 weeks' gestation with respect to younger gestational ages. No perinatal deaths occurred among the study cases. CONCLUSIONS: A "break point" in neonatal morbidity was observed at 34 weeks' gestation, which supports induction of labor at this gestational age. The short latencies observed limit the potential benefits of expectant management.

Neonatal outcomes in triplet gestations after a trial of labor.

OBJECTIVE: This study aimed to compare neonatal outcomes in a cohort of triplet gestations undergoing a trial of labor with those of a similar cohort delivered by elective cesarean delivery. STUDY DESIGN: Thirty-three women with triplet gestations who underwent a trial of labor were compared with a matched cohort of 33 women with triplet gestations who were delivered of their infants by elective cesarean delivery. Neonatal outcomes assessed included respiratory distress syndrome, retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage, Apgar scores, and birth trauma. RESULTS: Twenty-nine of 33 women (87.9%) who underwent a trial of labor had a successful vaginal delivery of all 3 neonates. One patient was delivered of her first triplet vaginally but then required a cesarean delivery for abruptio placentae; 3 other patients were delivered of their infants by cesarean section for active-phase arrest of labor. There were no differences in neonatal outcomes between the 2 groups, although triplet neonates delivered by elective cesarean section demonstrated a trend toward a greater incidence of respiratory distress syndrome (P = .09). CONCLUSION: Our experience suggests that offering vaginal delivery is an acceptable management plan for triplet gestations.

Perinatal outcome associated with outpatient management of triplet pregnancy.

OBJECTIVE: Our goal was to compare the lengths of hospitalization and the perinatal outcomes of triplet pregnancies managed with either outpatient or inpatient third-trimester bed rest. STUDY DESIGN: Thirty-two triplet pregnancies in which outpatient bed rest was prescribed (April 1993 to April 1996) were compared with a historic cohort of 34 triplets (January 1985 to March 1993) in which routine hospitalization was undertaken in the third trimester. Length of hospitalization and maternal and neonatal outcome parameters were compared between groups. RESULTS: Maternal inpatient hospital days were significantly reduced for the group managed as outpatients, but combined maternal and neonatal hospitalization was similar between groups. The mean gestational age at delivery was 1 week greater in the hospitalized cohort (33.5+/-2.8 vs 32.5+/-2.8, respectively; p=0.16), and average birth weight was correspondingly greater in hospitalized cases (1942 gm vs 1718 gm, p < 0.005). Neonatal lengths of stay were similar between groups, reflecting earlier postnatal discharge in the outpatient era of this study. Preeclampsia occurred with greater frequency in the outpatient group (31.3% vs 8.8%, p=0.02), and the neonatal complication of intraventricular hemorrhage occurred more commonly in this cohort as well (10/96 vs 1/102, p=0.004). All other maternal and neonatal complications were similar between groups. CONCLUSION: Reduction in the length of hospitalization attributable to outpatient management was limited to the maternal length of stay. It is possible that the observed maternal and neonatal complications in the outpatient group may have been related to less rigorous bed rest. We would suggest that the differences noted in preeclampsia, birth weight, and intraventricular hemorrhage support prospective evaluation of bed rest in triplet pregnancy.

The haemostatic effectiveness of autologous platelet rich plasma sequestered after heparin administration and institution of cardiopulmonary bypass.

Preoperative harvesting and postoperative reinfusion of autologous platelet rich plasma (PRP) has been reported to decrease blood loss as well as the requirement for homologous blood transfusion following cardiopulmonary bypass (CPB). We have developed a technique of intraoperative PRP sequestration which occurs during the initial period of CPB after the patient's circulation is supported and heparin has been given (PRP+). This process does not require any additional hardware, personnel or expense and it is performed without difficulty or complication. To evaluate the effect of PRP+ sequestration and reinfusion on blood loss and homologous blood requirement after CPB, we randomly assigned 126 consecutive patients undergoing elective open heart surgery into the experimental group 1 (PRP+) (n = 64) or the control (no platelet pheresis) group 2 (n = 52). A third group (n = 10) were not included in the randomization. Patients in group 3 had PRP prepared by conventional techniques (PRPc) prior to heparin administration and given to the patient after protamine infusion. Aggregation and activation studies were performed on the PRP+, PRPc, and blood bank platelets (BBP). Per cent aggregation of PRP in response to ADP was superior to that of BBP. There were no significant differences in ADP induced aggregation between PRP+ and PEPc. There was no significant difference in platelet activation (CD62) or number between the three groups. Patients infused with PRP+ showed significantly increased aggregation to ADP when compared with untreated patients 120 minutes after return to the ICW. Furthermore, more homologous haemostatic components (platelets/fresh frozen plasma) were required in the control group. We have demonstrated that collection of autologous PRP+ after administration of heparin does not interfere with its haemostatic effectiveness compared with PRPc prepared before the initiation of bypass. Moreover, this can be performed universally in haemodynamically unstable patients without any additional costs.